Trp-p8 active compounds and therapeutic treatment methods

Abstract

Compounds of the disclosure provide compositions, which are effective for prophylaxis and treatment of diseases or disorders, such as cell-proliferation, angiogenesis, or apoptosis mediated diseases. The disclosure encompasses compounds, analogs, prodrugs, metabolites, and pharmaceutically acceptable salts thereof, pharmaceutical compositions, and methods for prophylaxis and treatment of diseases and other maladies or conditions involving cancer, tumors, and like conditions. The disclosure also provides therapeutic methods including the administration of an effective amount of a compound of the disclosure.

The claimed invention is: 
     
         1 . A compound of the formula IIa: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, or (C 1 -C 6 )alkyl; 
         R 2  is phenyl or a substituted phenyl of the formula (-PhR 3 R 4 R 5 R 6 R 7 ) 
       
       
         
           
           
               
               
           
         
         where 
         R 3 , R 4 , R 6 , and R 7  are each independently —H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxyl, or halo; 
         R 5  is halo, (C 1 -C 6 )alkyl, (C 3 -C 12 )cycloalkyl, (C 1 -C 6 )alkoxyl, —C(═O)(C 1 -C 6 )alkyl or (C 1 -C 7 )alkanoyl; 
         or R 5  is —NR 8 R 9 , where R 8  and R 9  are each independently —H, (C 1 -C 6 )alkyl, or R 8  and R 9  together with the nitrogen to which they are attached form a morpholino, pyrrolidino, piperidino, piperzino, indolino, benzimidazolino, azetidino, aziridino, azepino, 1,4-oxazino, or thiomorpholino ring; 
         or R 4  and R 5  together with the phenyl to which they are attached form a ring having 4 to 7 atoms and the ring having from 1 to 3 unsaturations; and 
         stereoisomeric forms, mixtures of stereoisomeric forms; 
         or a pharmaceutically acceptable salt thereof, 
         provided that when R 3 , R 4 , R 6 , and R 7  of -PhR 3 R 4 R 5 R 6 R 7  are —H, R 5  is other than —CH 3 , —OCH 3 , —OH, —F, or —NO 2 ; and 
         provided that R 2  is other than 3-hydroxy-4-methyl-phenyl; and further provided that R 2  is other than 2-hydroxy-naphthyl, or pyridyl. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound of the formula (IIa) is:
 2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (4-morpholin-4-yl-phenyl)-amide;   2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (3-chloro-4-methoxy-phenyl)-amide;   2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (4-sec-butyl-phenyl)-amide;   2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (4-tert-butyl-phenyl)-amide;   2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (4-propyl-phenyl)-amide; and   2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (4-isopropyl-3-methyl-phenyl)-amide, or pharmaceutically acceptable salts thereof.   
     
     
         3 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         4 . The composition of  claim 3 , further comprising an effective amount of at least one additional chemotherapeutic agent for treating or preventing a disease or Trp-p8 receptor related condition. 
     
     
         5 . The composition of  claim 4 , wherein the chemotherapeutic agent is an antibody that causes apoptosis, inhibits angiogenesis, or both. 
     
     
         6 . The composition of  claim 5 , wherein the chemotherapeutic agent is an anti-VEGF antibody. 
     
     
         7 . A method of treating cancer comprising contacting the cancer cells comprising a Trp-p-8 receptor with an effective amount of a compound of  claim 1 . 
     
     
         8 . A method of treating cancer comprising contacting the cancer cells comprising a Trp-p-8 receptor with an effective amount of a pharmaceutical composition of  claim 3 .